Summary of Work: We continue to examine the possible role of genetic susceptibility in the etiology of lung cancer in two studies. The first is case-control study of African-Americans and Caucasians in Los Angeles County (356 cases and 731 controls). During this year we submitted manuscript on polymorphisms of three cytochome P450s - CYP2A6, CYP2D6 and CYP2C9. Our data suggest a possible decreased risk of lung cancer among subjects with CYP2A6 variant alleles that will require confirmation in larger studies. For CYP2D6, we did not confirm the strong associations seen with enzyme activity assays in two early studies but found that duplication of the CYP2D6 gene, which produces rapid metabolism, may be a risk factor. A suggestive finding for the CYP2C9 polymorphism seen when we examined only the CYP2C9*2 allele was not confirmed when we extended our laboratory analysis to the newly discovered *3 allele. In addition, we developed an RFLP/PCR analysis to detect a recently described functionally significant polymorphism in the promoter region of the myeloperoxidase (MPO) gene. Subjects with two copies of the MPO variant allele associated with reduced activity may be at decreased risk of lung cancer. This result is of interest because myeloperoxidase is present in higher concentration in the lung than most of the cytochrome P450s, is capable of metabolic activation of a number of carcinogens and catalyzes endogenous production of free radicals. We continue to collect tissue blocks to be used to examine mutations in critical target genes. The second population we are studying is a cohort of 18,000 men in Shanghai. We are examining polymorphisms of CYP1A1, GSTM1 and GSTT1 in relation to lung cancer risk in collaboration with investigators at USC where the study is based. We are following up an interesting finding of an association primarily seen among lighter smokers for the GSTM1 null genotype in the Shanghai cohort which as a large proportion of light smokers. In the next year, we plan to examine newly described polymorphisms of DNA repair genes in relation to lung cancer risk.